Introduction

Uses for Geodon

Schizophrenia

Orally for acute and maintenance treatment of schizophrenia in adults.1236712115

IM injection used for management of acute agitation in adults with schizophrenia for whom treatment with ziprasidone is appropriate and who require an IM antipsychotic agent for rapid control of behaviors that interfere with diagnosis and care (e.g., threatening behaviors, escalating or urgently distressing behavior, self-exhausting behavior).1

American Psychiatric Association (APA) considers most atypical antipsychotic agents first-line drugs for management of the acute phase of schizophrenia (including first psychotic episodes).29

Patients who do not respond to or tolerate one drug may be successfully treated with an agent from a different class or with a different adverse effect profile.29707172

When deciding among treatment alternatives, consider that ziprasidone may prolong the QT interval.1 Some other drugs that prolong the QT interval cause torsades de pointes-type arrhythmia; it is not yet known whether ziprasidone causes torsades de pointes or increases the rate of sudden death.1 In many cases, other drugs should be tried first.1 (See Prolongation of QT Interval and Risk of Sudden Death under Cautions.)

Bipolar Disorder

Orally for acute treatment (as monotherapy) of manic or mixed episodes (with or without psychotic features) associated with bipolar I disorder in adults.17374

Orally for maintenance treatment (as adjunct to lithium or valproate) of bipolar I disorder in adults.1792103

When deciding among treatment alternatives, consider that ziprasidone may prolong the QT interval.1 Some other drugs that prolong the QT interval cause torsades de pointes-type arrhythmia; it is not yet known whether ziprasidone causes torsades de pointes or increases the rate of sudden death.1 In many cases, other drugs should be tried first.1 (See Prolongation of QT Interval and Risk of Sudden Death under Cautions.)

Oral Administration

IM Administration

Reconstitution

Reconstitute vial containing 20 mg with 1.2 mL of sterile water for injection to provide a solution containing 20 mg/mL.1 Do not use other solutions to reconstitute the injection, and do not admix with other drugs.1 Shake vigorously to ensure complete dissolution.1

Dosage

Available as ziprasidone hydrochloride or ziprasidone mesylate; dosage of ziprasidone hydrochloride expressed in terms of the hydrochloride monohydrate and dosage of ziprasidone mesylate expressed in terms of ziprasidone.112

Adults

Schizophrenia

Acute and Maintenance Therapy

Oral

Initially, 20 mg twice daily.1 In some patients, may adjust dosage based on clinical status up to 80 mg twice daily.1

Dosage adjustments, if indicated, generally should be made after a minimum of 2 days.112 However, manufacturer recommends observing patients for several weeks prior to upward titrations of dosage to ensure use of the lowest effective dosage.1 Dosages ranging from 20–100 mg twice daily were effective in short-term controlled studies.1 Although there were trends toward a dose response within a dosage range of 20–80 mg twice daily, results were not consistent.1

Optimum duration of therapy not known, but efficacy maintained for up to 52 weeks in a clinical trial.1115 In patients responding to ziprasidone therapy, continue the drug as long as clinically necessary and tolerated, but at lowest possible effective dosage;12 periodically reassess need for continued therapy.1

In patients with remitted first or multiple episodes, APA recommends either indefinite maintenance therapy or gradual discontinuance of the antipsychotic with close follow-up and a plan to reinstitute treatment upon symptom recurrence.29 Consider antipsychotic therapy discontinuance only after ≥1 year of symptom remission or optimal response while receiving the drug.29 Indefinite maintenance treatment recommended if patient has experienced multiple previous psychotic episodes or 2 episodes within 5 years.29

Contraindications

Concomitant therapy with drugs that prolong the QT interval.1 (See Prolongation of QT Interval and Risk of Sudden Death under Cautions and also see Drugs that Prolong QT Interval and Specific Drugs under Interactions.)

Warnings/Precautions

Warnings

Increased risk of death with use of either conventional (first-generation) or atypical (second-generation) antipsychotics in geriatric patients with dementia-related psychosis.16878

Antipsychotic agents, including ziprasidone, are not approved for the treatment of dementia-related psychosis.16878 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning and also see Dysphagia under Cautions.)

Other Warnings and Precautions

Prolongation of QT Interval and Risk of Sudden Death

Greater capacity to prolong the QT/QTc (corrected QT) interval compared with that of several other antipsychotic agents (e.g., haloperidol, olanzapine, quetiapine, risperidone).129 No cases of torsades de pointes reported with ziprasidone during premarketing clinical trials; however, rare postmarketing cases of torsades de pointes (in the presence of multiple confounding factors) reported with the drug.1

Sudden unexplained deaths have been reported in patients receiving ziprasidone or other antipsychotic agents at recommended dosages.1 Although premarketing experience with ziprasidone did not demonstrate an excess risk of mortality compared with that of other antipsychotic agents, the extent of exposure was limited.1 The greater risk of QT-interval prolongation compared with several other antipsychotic agents raises the possibility that the risk of sudden death may be greater with ziprasidone than for other antipsychotic agents.1 This possibility should be considered in deciding among alternative antipsychotic agents.1 (See Uses.)

Factors that may increase the risk of torsades de pointes and/or sudden death include bradycardia, hypokalemia or hypomagnesemia; concomitant use of other drugs that prolong the QT interval; and congenital prolongation of the QT interval.1 Avoid use in patients with a history of clinically important cardiovascular disease (e.g., congenital prolongation of the QT interval, QT-interval prolongation, recent AMI, uncompensated heart failure, history of cardiac arrhythmias) and in those concurrently receiving other drugs that prolong the QTc interval.1 (See Contraindications under Cautions and also see Drugs that Prolong QT Interval and Specific Drugs under Interactions.)

Immediately discontinue therapy and initiate supportive and symptomatic treatment if NMS occurs.1 Careful monitoring recommended if therapy is reinstituted following recovery; the risk that NMS can recur must be considered.1

Severe Cutaneous Adverse Reactions

Drug reaction with eosinophilia and systemic symptoms (DRESS; also known as multiorgan hypersensitivity reaction) reported.1108116 DRESS, which is fatal in some cases, consists of a combination of 3 or more of the following: cutaneous reaction (e.g., rash, exfoliative dermatitis), eosinophilia, fever, lymphadenopathy, and one or more systemic complications (e.g., hepatitis, nephritis, pneumonitis, myocarditis, pericarditis, pancreatitis).1108

In an FDA review of 6 cases of DRESS associated with ziprasidone use worldwide, onset of DRESS symptoms occurred 11–30 days after initiation of therapy.108 In 3 of the cases, discontinuance and reinitiation of the drug resulted in recurrence of symptoms with a faster time to onset.108 In half of the cases, other drugs associated with DRESS were used concomitantly.108 Serious outcomes, including hospitalization, occurred, but no deaths were reported.108

Tardive Dyskinesia

Tardive dyskinesia, a syndrome of potentially irreversible, involuntary dyskinetic movements, reported with use of antipsychotic agents, including ziprasidone.183848586878889

Reserve long-term antipsychotic treatment for patients with chronic illness known to respond to antipsychotic agents, and for whom alternative, equally effective, but potentially less harmful treatments are not available or appropriate.1 In patients requiring chronic treatment, use smallest dosage and shortest duration of treatment producing a satisfactory clinical response; periodically reassess need for continued therapy.1

APA recommends assessing patients receiving atypical antipsychotic agents for abnormal involuntary movements every 12 months; for patients at increased risk for tardive dyskinesia, assess every 6 months.29 Consider discontinuance of ziprasidone if signs and symptoms of tardive dyskinesia appear.1 However, some patients may require treatment despite presence of the syndrome.1

Metabolic Changes

Atypical antipsychotic agents are associated with metabolic changes that may increase cardiovascular and cerebrovascular risk (e.g., hyperglycemia, dyslipidemia, weight gain).1 While all atypical antipsychotics produce some metabolic changes, each drug has its own specific risk profile.1 (See Hyperglycemia and Diabetes Mellitus, see Dyslipidemia, and also see Weight Gain under Cautions.)

Hyperglycemia and Diabetes Mellitus

Hyperglycemia, sometimes severe and associated with ketoacidosis, hyperosmolar coma, or death, reported in patients receiving atypical antipsychotic agents.113141617181920212223242526404142434767 There have been few reports of hyperglycemia or diabetes in ziprasidone-treated patients; not known whether paucity of such reports is due to relatively limited experience with the drug.1162025606162636465

Closely monitor patients with diabetes mellitus for worsening of glycemic control, and perform fasting glucose testing at baseline and periodically in patients with risk factors for diabetes (e.g., obesity, family history of diabetes).1131416171819202122232425 If manifestations of hyperglycemia occur in any ziprasidone-treated patient, perform fasting blood glucose testing.1131416171819202122232425

Some patients who developed hyperglycemia while receiving an atypical antipsychotic have required continuance of antidiabetic treatment despite discontinuance of the suspect drug; in other patients, hyperglycemia resolved with discontinuance of the antipsychotic.113141617181920212223242547

Dyslipidemia

Undesirable changes in lipid parameters observed in patients treated with atypical antipsychotics; however, ziprasidone generally does not adversely affect the lipid profile in most patients.129

Weight Gain

Weight gain observed with atypical antipsychotic therapy.1 Although ziprasidone generally appears to be associated with no or minimal weight gain and has a lower risk of weight gain than some other atypical antipsychotic agents (e.g., clozapine, olanzapine, quetiapine, risperidone),129 manufacturer recommends clinical monitoring of weight in patients receiving the drug.1

Rash

Rash and/or urticaria, possibly related to dosage and/or duration of therapy, occurred in about 5% of patients in premarketing clinical studies and necessitated discontinuance of the drug in about 17% of these patients.1 Several patients with rash had signs and symptoms of associated systemic illness (e.g., elevated WBC count).1

Possible risk factors for leukopenia and neutropenia include preexisting low WBC count and history of drug-induced leukopenia or neutropenia.198 Monitor CBC frequently during the first few months of therapy in patients with such risk factors.1 Discontinue ziprasidone at the first sign of a decline in WBC count in the absence of other causative factors.1

Carefully monitor patients with neutropenia for fever or other signs and symptoms of infection and treat promptly if they occur.1 In patients with severe neutropenia (ANC <1000/mm3), discontinue ziprasidone and monitor WBC until recovery occurs.1

Seizures

Seizures reported in 0.4% of ziprasidone-treated patients in clinical trials.1

Use with caution in patients with a history of seizures or with conditions that may lower the seizure threshold (e.g., dementia of the Alzheimer’s type); conditions that lower seizure threshold may be more prevalent in patients ≥65 years of age.1

Dysphagia

Esophageal dysmotility and aspiration associated with the use of antipsychotic agents.1

Aspiration pneumonia is a common cause of morbidity and mortality in geriatric patients, particularly in those with advanced Alzheimer's dementia.1 Use with caution in patients at risk for aspiration pneumonia.1 (See Increased Mortality in Geriatric Patients with Dementia-related Psychosis in Boxed Warning.)

Hyperprolactinemia

May cause elevated serum prolactin concentrations, which may lead to clinical disturbances (e.g., galactorrhea, amenorrhea, gynecomastia, impotence); chronic hyperprolactinemia associated with hypogonadism may lead to decreased bone density.1

If contemplating ziprasidone therapy in a patient with previously detected breast cancer, consider that approximately one-third of human breast cancers are prolactin dependent in vitro.1

Cognitive and Motor Impairment

Somnolence reported in 14% of ziprasidone-treated patients during short-term clinical trials; somnolence may be dose related.1 Judgment, thinking, or motor skills may be impaired.1 (See Specific Drugs under Interactions and also see Advice to Patients.)

Priapism

Priapism reported in several ziprasidone-treated patients.1110111112113114 May require surgical intervention in severe cases.1112

Body Temperature Regulation

Use appropriate caution in patients who will be experiencing conditions that may contribute to an elevation in core body temperature (e.g., strenuous exercise, extreme heat, concomitant use of agents with anticholinergic activity, dehydration).1

Suicide

Attendant risk with psychotic illness and bipolar disorder; closely supervise high-risk patients.1 Prescribe in the smallest quantity consistent with good patient management to reduce the risk of overdosage.1

Concomitant Illness

Limited experience with ziprasidone in patients with certain concomitant diseases.1

Not adequately evaluated in patients with a recent history of MI or unstable cardiovascular disease; use with caution in cardiac patients.1 (See Contraindications under Cautions, see Prolongation of QT Interval and Risk of Sudden Death under Cautions, and also see Orthostatic Hypotension under Cautions.)

Lactation

Manufacturer states not known whether ziprasidone or its metabolites are distributed into milk.1 However, a low concentration of ziprasidone was reported in milk and also in the plasma of one breast-fed infant.109 (See Distribution under Pharmacokinetics.) Women receiving ziprasidone should not breast-feed.1

Pediatric Use

Safety and efficacy not established in pediatric patients <18 years of age.1

Geriatric Use

No substantial differences in safety or efficacy of oral ziprasidone relative to younger adults; however, possibility of greater sensitivity in some geriatric patients cannot be ruled out.1

Risk of increased pharmacodynamic response, poorer tolerance, or orthostasis; lower initial dosages, slower titration, and careful monitoring during the initial dosing period may be advisable in some geriatric patients.1

Geriatric patients with dementia-related psychosis treated with either conventional or atypical antipsychotic agents are at an increased risk of death.16878 Substantial (1.6- to 1.7-fold) increase in mortality rate reported in geriatric patients with dementia who received atypical antipsychotic agents (e.g., aripiprazole, olanzapine, quetiapine, risperidone) for treatment of behavioral disorders; most fatalities resulted from cardiac-related events (e.g., heart failure, sudden death) or infections (mostly pneumonia).168 Ziprasidone is not approved for the treatment of patients with dementia-related psychosis.1 (See Boxed Warning and Increased Mortality in Geriatric Patients with Dementia-related Psychosis under Cautions.)

Renal Impairment

Renal impairment alone unlikely to substantially affect pharmacokinetics of oral ziprasidone.1 Dosage adjustment based on degree of renal impairment not necessary.1 (See Special Populations under Pharmacokinetics.)

IM ziprasidone not studied in patients with renal impairment.1 Commercially available ziprasidone mesylate injections contain sulfobutylether β-cyclodextrin sodium, an excipient that is cleared by renal filtration; use with caution.1

Interactions for Geodon

Ziprasidone is metabolized by the CYP3A4 isoenzyme; CYP1A2 also may contribute but to a much lesser extent.1 Little inhibitory effect on CYP isoenzymes 1A2, 2C9, 2C19, 2D6, or 3A4; pharmacokinetic interaction unlikely with drugs metabolized by these isoenzymes.1

Drugs Affecting Hepatic Microsomal Enzymes

Pharmacokinetic interaction with inhibitors or inducers of CYP1A2, CYP2C9, CYP2C19, or CYP2D6 are unlikely.1

Drugs that Prolong QT Interval

Potential additive effect on QT-interval prolongation (concomitant use contraindicated) when used with drugs that prolong the QT interval.1 Ziprasidone also is contraindicated in patients receiving drugs shown to cause QT prolongation as an effect and for which this effect is described in the full prescribing information as a contraindication or boxed or bolded warning.1 (See Contraindications and Prolongation of QT Interval and Risk of Sudden Death under Cautions.)

Food

Special Populations

Mean AUC was 13 and 34% higher in individuals with Child-Pugh class A and B hepatic impairment, respectively, compared with that of those in the control group.1

Distribution

Extent

Manufacturer states not known whether the drug or its metabolites are distributed into milk in humans.1 However, a low concentration of ziprasidone in milk was reported in one woman; the milk/plasma ratio was 0.06 and the relative infant dose was estimated to be 1.2% of the weight-normalized maternal dose.109

Plasma Protein Binding

Elimination

Metabolism

Extensively metabolized in the liver. principally via reduction by aldehyde oxidase; about one-third of metabolic clearance is mediated by CYP isoenzymes, principally CYP3A4.1

Elimination Route

Approximately 20% of a dose is excreted in the urine and about 66% in feces, principally as metabolites.1 Not removed by hemodialysis.1

Half-life

Mean terminal half-life following oral administration is about 7 hours;1 following IM administration, the half-life is 2–5 hours.1

Special Populations

In patients with clinically important (Child-Pugh class A or B) cirrhosis, half-life increased by 2.3 hours compared with that of patients in the control group.1

Pharmacokinetics of oral ziprasidone similar among individuals with varying degrees of renal impairment and those with normal renal function.1 IM ziprasidone not studied in patients with renal impairment.1

Does not possess appreciable affinity for other receptors or binding sites, including muscarinic receptors.1

Advice to Patients

Importance of providing a copy of written patient information (medication guide) each time oral ziprasidone is dispensed.1 Importance of advising patients to read the patient information before taking ziprasidone.1

Importance of taking ziprasidone exactly as prescribed.1 Importance of informing patients to swallow ziprasidone capsules whole and to take with food for optimal absorption, preferably at the same time each day.1

Importance of advising patients and caregivers that geriatric patients with dementia-related psychosis treated with antipsychotic agents are at an increased risk of death.1296878 Inform patients and caregivers that ziprasidone is not approved for treating geriatric patients with dementia-related psychosis.168

Importance of patients informing their clinician if they have the following: history of QT-interval prolongation or cardiac arrhythmia, recent AMI, uncompensated heart failure, risk for clinically important electrolyte abnormalities, or are receiving other drugs that may prolong the QT interval.1 (See Contraindications under Cautions and see Drugs that Prolong QT Interval and Specific Drugs under Interactions.)

Importance of patients informing their clinician of the onset of conditions that may increase the risk for clinically important electrolyte disturbances (e.g., hypokalemia) such as the initiation of diuretic therapy or prolonged diarrhea or vomiting; importance of reporting symptoms possibly associated with torsades de pointes (e.g., dizziness, palpitations, syncope) to the clinician.1

Risk of severe cutaneous adverse reactions, such as DRESS or Stevens-Johnson syndrome.1108 Importance of advising patients to notify their clinician at the earliest onset of any manifestations, including rash, fever, swollen face, or swollen lymph nodes.1108

Risk of hyperglycemia in patients receiving atypical antipsychotics.1 Importance of patients and caregivers being aware of the symptoms of hyperglycemia and diabetes mellitus (e.g., increased thirst, increased urination, increased appetite, weakness) and monitoring all patients receiving ziprasidone for these symptoms.1 Importance of informing patients with diabetes or those with risk factors for diabetes (e.g., obesity, family history of diabetes) that they should have their blood glucose monitored at the beginning of and periodically during ziprasidone therapy; patients who develop symptoms of hyperglycemia during therapy should have their blood glucose assessed.1

Risk of leukopenia/neutropenia.1 Importance of advising patients with a preexisting low WBC count or history of drug-induced leukopenia/neutropenia of the need for CBC monitoring during ziprasidone therapy.1

Importance of clinicians informing patients in whom chronic ziprasidone use is contemplated about the risk of tardive dyskinesia.1107 Importance of informing patients to report any abnormal muscle movements to a healthcare professional.107

Risk of NMS, which can cause high fever, stiff muscles, sweating, fast or irregular heart beat, change in BP, confusion, and kidney damage.1

Importance of informing patients that the effects of oral ziprasidone may take a few weeks to be evident and to continue ziprasidone therapy even if improvement is not noticed immediately.1 Importance of patients continuing to take oral ziprasidone even if improvement is seen, unless directed otherwise by their clinician.1

Risk of orthostatic hypotension and dizziness or syncope (fainting), particularly during the initial dosage titration period or when the dosage is increased.1 Importance of informing patients about interventions that may help to reduce the occurrence of orthostatic hypotension (e.g., slowly rising from a seated position) and to contact their clinician if dizziness or fainting occurs.1

Importance of women informing clinicians if they are or plan to become pregnant or plan to breast-feed.1106 Importance of clinicians informing patients about the benefits and risks of taking antipsychotics during pregnancy (see Pregnancy under Cautions).1106 Importance of advising patients not to stop taking ziprasidone if they become pregnant without consulting their clinician; abruptly stopping antipsychotic agents may cause complications.106 Importance of advising patients not to breast-feed during ziprasidone therapy.1

26. American Diabetes Association; American Psychiatric Association; American Association of Clinical Endocrinologists; North American Association for the Study of Obesity.. Consensus development conference on antipsychotic drugs and obesity and diabetes. Diabetes Care. 2004; 27:596-601. http://www.ncbi.nlm.nih.gov/pubmed/14747245?dopt=AbstractPlus

77. Banerjee S. The use of antipsychotic medication for people with dementia: time for action; a report for the Minister of State for Care Services. United Kingdom Department of Health. From the website. https://www.gov.uk/government/organisations/department-of-health-and-social-care